Valentine W M, Schaeffer D J, Beasley V R
Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana 61801.
Toxicon. 1991;29(3):347-57. doi: 10.1016/0041-0101(91)90288-3.
The indirectly evoked compound action potentials (ECAP) of the plantar muscles of the rat were used to investigate the pharmacodynamics in vivo of the neuromuscular blockade produced by anatoxin-a. Onset time to maximum depression and the magnitude of maximum depression in amplitude of the ECAP were dose-dependent. The mean maximum percent depression (+/- S.D.) of the ECAP induced by single, supramaximal stimulations of the posterior tibial nerve after i.v. doses of (+)anatoxin-a hydrochloride at 0, 50, 100, 200 and 800 micrograms/kg were 3 (4), 53 (15), 82 (7), 95 (2), and 100 (1), respectively. The ED50 (95% confidence limits) for depression of the ECAP was 47 mg/kg (39-57 micrograms/kg). Rats administered 200 micrograms/kg or less of (+)anatoxin-a hydrochloride had 75% return of the pretoxin amplitude of the ECAP within 93 min. Animals dosed at 800 micrograms/kg did not have return of neuromuscular function and died despite mechanical ventilation, suggesting a lethal mechanism(s) of action in addition to respiratory paralysis. Percent decrements (+/- S.D.) in the amplitude of the fourth ECAP following repetitive stimulation at 10 Hz were 6 (5), 13 (22), 46 (18) and 59 (8) from (+)anatoxin-a hydrochloride given i.v. at 0, 50, 100 and 200 micrograms/kg, respectively. The decrement observed following repetitive stimulation was attributed to a presynaptic site of action. No change in maximal motor nerve conduction velocity or latency of the ECAP was observed after i.v. administration of (+)anatoxin-a hydrochloride at 100 micrograms/kg. LD50 values (95% confidence limits) for anatoxin-a administered i.v. to mice were 386 micrograms/kg (365-408 micrograms/kg, for (+)anatoxin-a hydrochloride and 913 micrograms/kg (846-985 micrograms/kg) for racemic anatoxin-a hydrochloride. No deaths were observed in mice after i.p. administration of (-)anatoxin-a hydrochloride at doses up to 73 mg/kg.
利用大鼠足底肌肉的间接诱发复合动作电位（ECAP）来研究anatoxin-a产生的神经肌肉阻滞在体内的药效学。ECAP达到最大抑制的起效时间和最大抑制幅度呈剂量依赖性。静脉注射0、50、100、200和800微克/千克的（+）盐酸anatoxin-a后，单次超强刺激胫后神经诱发的ECAP平均最大抑制百分比（±标准差）分别为3（4）、53（15）、82（7）、95（2）和100（1）。ECAP抑制的半数有效量（ED50，95%置信限）为47微克/千克（39 - 57微克/千克）。静脉注射200微克/千克或更低剂量（+）盐酸anatoxin-a的大鼠，其ECAP的毒素前幅度在93分钟内有75%恢复。给予800微克/千克剂量的动物，神经肌肉功能未恢复，尽管进行了机械通气仍死亡，这表明除呼吸麻痹外还存在致死作用机制。静脉注射0、50、100和200微克/千克（+）盐酸anatoxin-a后，在10赫兹重复刺激下，第四个ECAP幅度的百分比衰减（±标准差）分别为6（5）、13（22）、46（18）和59（8）。重复刺激后观察到的衰减归因于突触前作用位点。静脉注射100微克/千克（+）盐酸anatoxin-a后，未观察到ECAP的最大运动神经传导速度或潜伏期有变化。静脉注射anatoxin-a给小鼠的半数致死量（LD50，95%置信限），（+）盐酸anatoxin-a为386微克/千克（365 - 408微克/千克），消旋盐酸anatoxin-a为913微克/千克（846 - 985微克/千克）。腹腔注射高达73毫克/千克剂量的（-）盐酸anatoxin-a后，小鼠未观察到死亡。
